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Imperial > 41. Cardiovascular Pathology > Flashcards

41. Cardiovascular Pathology Flashcards

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1
Q
A
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2
Q

State the steps involved in haemostatic plug formation from the time of injury.

A

Vessel constriction Formation of an unstable platelet plug (platelet adhesion + platelet aggregation) Stabilisation of plug with fibrin (blood coagulation) Dissolution of clot and vessel repair (fibrinolysis)

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3
Q

What component found underneath the endothelium is involved in triggering the coagulation cascade?

A

Procoagulant subendothelial structures e.g. collagen Tissue factor is also expressed on the surface of the cell that underlie blood vessels but it is NOT normally expressed within the circulation itself

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4
Q

State some important factors produced by endothelial cells.

A

Prostacyclin Thrombomodulin Von Willebrand Factor Plasminogen Activator

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5
Q

What do the dense granules in platelets contain that is important for platelet function?

A

ADP

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6
Q

What do alpha granules in the platelets contain?

A
  • vWF
  • Factor V
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7
Q

State the two ways in which platelets can bind to collagen. Name the receptors involved.

A

It can bind via vWF to collagen (via the GlpIb receptor) It can bind directly to the collagen (via the GlpIa receptor)

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8
Q

What happens following the passive adhesion of platelets andengagement of receptors?

A

The receptors signal inside the cell to release ADP from the storage granules and to synthesise thromboxane These bind to receptors on the surface of the platelets and activate them Once activated, GlpIIb/IIIa receptors become available, which can bind to fibrinogen and allows the platelets to aggregate

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9
Q

Which receptors on the platelets become available following activation of the platelets and what do they bind to?

A

GlpIIb/IIIa These bind to fibrinogen

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10
Q

What else can activate platelets?

A

Thrombin

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11
Q

What percentage of the blood volume is made up of red blood cells?

A

Around 45%

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12
Q

What normally has to be damaged for a thrombus to form?

A

Tunica intima

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13
Q

What is the difference between red and white thrombi?

A

Red – forms in veins – rich in fibrin and red blood cells White – forms in arteries – rich in platelets and macrophages (foam cells)

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14
Q

What are the three parts of Virchow’s triad?

A

Stasis Vessel wall injury Hypercoagulability/consistency of blood (balance between procoagulants and anti-coagulants)

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15
Q

What are the three stages in the cell based theory of coagulation? State which types of drugs target each of the different stages.

A

Initiation – small-scale production of thrombin – ANTI-COAGULANTS Amplification – large-scale thrombin production on the surface of platelets – ANTI-PLATELETS Propagation – thrombin mediated generation of fibrin strands - THROMBOLYTICS

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16
Q

What does the tissue factor-bearing cell contain?

A

Tissue Factor Prothrombinase Complex = Factor 5a + Factor 10a

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17
Q

Describe the process of initiation.

A

TF bearing cells activate factor 5 and factor 10 forming the prothrombinase complex (5a + 10a) The prothrombinase complex converts prothrombin to thrombin

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18
Q

What is responsible for the inactivation of factors 2a and 10a?

A

Antithrombin (AT-III)

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19
Q

State some drugs that target the initiation stage of coagulation.

A

Dabigatran – factor 2a inhibitor (oral – NOAC) Rivaroxaban – factor 10a inhibitor (oral – NOAC) Heparin – potentiates antithrombin – less 2a + 10a (IV/SC) Low Molecular Weight Heparin (e.g. Dalteparin) – activates antithrombin – preferentially targets factor 10a Warfarin – vitamin K epoxide reductase inhibitor – inhibits the production of factors 2, 7, 9 and 10

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20
Q

What are the indications of these anti-coagulants?

A

Venous thromboembolism (DVT + PE) Prevent thrombosis during surgery Atrial fibrillation – prophylaxis of stroke

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21
Q

Describe the amplification stage of coagulation.

A

Thrombin activates platelets and makes them more sticky so that they aggregate

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22
Q

Explain, in detail, how thrombin causes platelet activation.

A

Thrombin binds to PAR (platelet activated receptor) on the platelet membrane This causes an increase in intracellular Ca2+ concentration This stimulates ADP exocytosis from dense granules The ADP then binds to P2Y12 receptors (ADP receptor) on the same platelet or on neighbouring platelets, which leads to platelet activation/aggregation Thrombin binding to the PAR also liberates arachidonic acid The arachidonic acid is converted by COX to thromboxane A2 Thromboxane A2 increases expression of GlpIIb/IIIa (which is involved in platelet aggregation)

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23
Q

State three drugs that target the amplification stage of coagulation and explain how they act.

A

Aspirin – irreversible COX1 inhibitor – it reduces the production of thromboxane by platelets Clopidogrel – irreversible ADP (P2Y12) receptor antagonist Abciximab – monoclonal antibodies directed at GlpIIb/IIIa

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24
Q

What are the indications of these anti-platelet drugs?

A

Arterial thrombosis:  Acute coronary syndromes – myocardial infarction  Atrial fibrillation – prophylaxis of stroke

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25
Describe the propagation stage of coagulation.
Thrombin converts fibrinogen to fibrin so fibrin strands are generated
26
Name an important thrombolytic and explain how it acts.
Alteplase – it is a recombinant tissue plasminogen activator (tPA) Plasminogen is converted to plasmin, which is a protease that degrades fibrin
27
What are the indications of thrombolytics?
First line treatment for stroke STEMI
28
What is a common site for the formation of deep vein thrombosis?
Popliteal veins
29
How can DVT and PE be treated, either prophylactically and after it has happened?
Prophylactically – anticoagulants After it happens – heparin or low MW heparin
30
What is an acute coronary syndrome?
Any condition brought on by sudden, reduced blood flow to the heart
31
What is NSTEMI?
Non-ST elevation myocardial infarction This is caused by partial occlusion of a coronary artery and it can lead to stable angina
32
Describe the management of NSTEMI.
Anti-platelets (e.g. clopidogrel and aspirin)
33
What is STEMI?
ST-elevation myocardial infarction This is caused by FULL occlusion of a coronary artery
34
Describe the management of STEMI.
Anti-platelet drugs Sometimes thrombolytics if the clot needs to be dissolved
35
What is the main difference in the composition of LDLs and HDLs?
They have different apoproteins
36
What is the main difference in the composition of LDLs and HDLs?
They have different apoproteins
37
What are dietary triglycerides and cholesterol packaged into once they are absorbed?
Chylomicrons
38
What are chylomicrons broken down into?
Chylomicron remnants
39
Are most circulating lipids endogenous or exogenous?
Endogenous
40
What is the significance of chylomicron remnants with regards to atherosclerosis?
They are very good at getting into the tunica intima
41
Define atherosclerosis.
Atherosclerosis is an inflammatory fibro-proliferative disorder
42
What cells are recruited in the process of atherosclerosis?
Macrophages (which turn into foam cells) Fibroblasts Smooth muscle cells
43
What must initially happen for the process of atherosclerosis to begin?
Increase in permeability of the endothelium Upregulation of leukocytes and cell adhesion molecules Migration of leukocytes into arterial wall
44
What can happen as the atheroma grows larger?
Some of the foam cells die and rupture, releasing their toxic contents to form a lipid necrotic core
45
Which cells are responsible for producing a protective fibrous cap over the fat core?
Smooth muscle cells lay down collagen fibres
46
What is an unstable atherosclerotic plaque?
The fibrous cap thins and eventually ruptures, exposing the thrombogenic lipid core to the platelets and coagulation factors This causes THROMBOSIS NOTE: plaque erosion is also associated with hardening of the arteries, leading to weakening and thickening of the vessel wall leading to aneurysm and possible haemorrhage
47
What do complicated lesions often contain?
Calcium
48
What are some characteristics of vulnerable plaques?
Thin fibrous cap A core rich in lipid and macrophages Less evidence of smooth muscle proliferation
49
What can modify LDL cholesterol?
Low HDL Diabetes Smoking Hypertension
50
What do low HDL cholesterol levels tend to be associated with?
High triglyceride levels
51
What factors can lower HDL cholesterol levels?
Smoking Obesity Physical inactivity
52
What is considered a normal triglyceride level?
\< 200 mg/dL or 2.3 mmol/L
53
Other than heart disease, what else is a very high triglyceride level associated with?
Pancreatitis
54
State some different drug therapies that have been used to treat high cholesterol.
Bile acid sequestrants Nicotinic acid Fibrates Statins
55
Describe the mechanism of action of statins.
They are HMG-CoA reductase inhibitors
56
What are two important products of the cholesterol synthesispathway?
Geranyl pyrophosphate Farnesyl pyrophosphate They are involved in the modification and activation of proteins
57
How do statins decrease plasma LDL levels?
Statins block the cholesterol synthesis pathway, which leads to the liver responding by producing more LDL receptors Having more LDL receptors means that more LDL can be removed from the blood
58
What is the selectivity ratio of a statin?
The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell
59
What is the Rule of 6?
Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol
60
How do fibrates act?
They activate PPAR-alpha They lower plasma fatty acids and lower triglycerides They are often used in diabetics with high triglycerides
61
Name an important drug that can be given with statins to further decrease LDL levels?
Ezetimibe – it inhibits cholesterol absorption
62
What is this drug activated as?
Glucuronide
63
Which protein is involved in the transport of cholesteryl esters and triglycerides from HDLs to LDLs?
Cholesteryl Ester Transfer Protein (CETP)
64
What was the result of attempted inhibition of CETP?
It increased HDL and decreased LDL but it had off target effects that led to increased mortality NOTE: the drug was called torcetrapib
65
What is PCSK9?
It is an inhibitor of LDL receptors It stops the LDL in the plasma from binding to the LDL receptor and being taken up PCSK9 inhibition can lead to a decrease in cholesterol levels
66
What are dietary triglycerides and cholesterol packaged into once they are absorbed?
Chylomicrons
67
What is PCSK9?
It is an inhibitor of LDL receptors It stops the LDL in the plasma from binding to the LDL receptor and being taken up PCSK9 inhibition can lead to a decrease in cholesterol levels
68
What was the result of attempted inhibition of CETP?
It increased HDL and decreased LDL but it had off target effects that led to increased mortality NOTE: the drug was called torcetrapib
69
Which protein is involved in the transport of cholesteryl esters and triglycerides from HDLs to LDLs?
Cholesteryl Ester Transfer Protein (CETP)
70
What is this drug activated as?
Glucuronide
71
Name an important drug that can be given with statins to further decrease LDL levels?
Ezetimibe – it inhibits cholesterol absorption
72
How do fibrates act?
They activate PPAR-alpha They lower plasma fatty acids and lower triglycerides They are often used in diabetics with high triglycerides
73
What is the Rule of 6?
Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol
74
What is the selectivity ratio of a statin?
The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell
75
How do statins decrease plasma LDL levels?
Statins block the cholesterol synthesis pathway, which leads to the liver responding by producing more LDL receptors Having more LDL receptors means that more LDL can be removed from the blood
76
What are two important products of the cholesterol synthesispathway?
Geranyl pyrophosphate Farnesyl pyrophosphate They are involved in the modification and activation of proteins
77
Describe the mechanism of action of statins.
They are HMG-CoA reductase inhibitors
78
State some different drug therapies that have been used to treat high cholesterol.
Bile acid sequestrants Nicotinic acid Fibrates Statins
79
Other than heart disease, what else is a very high triglyceride level associated with?
Pancreatitis
80
What is considered a normal triglyceride level?
\< 200 mg/dL or 2.3 mmol/L
81
What factors can lower HDL cholesterol levels?
Smoking Obesity Physical inactivity
82
What do low HDL cholesterol levels tend to be associated with?
High triglyceride levels
83
What can modify LDL cholesterol?
Low HDL Diabetes Smoking Hypertension
84
What are some characteristics of vulnerable plaques?
Thin fibrous cap A core rich in lipid and macrophages Less evidence of smooth muscle proliferation
85
What do complicated lesions often contain?
Calcium
86
What is an unstable atherosclerotic plaque?
The fibrous cap thins and eventually ruptures, exposing the thrombogenic lipid core to the platelets and coagulation factors This causes THROMBOSIS NOTE: plaque erosion is also associated with hardening of the arteries, leading to weakening and thickening of the vessel wall leading to aneurysm and possible haemorrhage
87
Which cells are responsible for producing a protective fibrous cap over the fat core?
Smooth muscle cells lay down collagen fibres
88
What can happen as the atheroma grows larger?
Some of the foam cells die and rupture, releasing their toxic contents to form a lipid necrotic core
89
What must initially happen for the process of atherosclerosis to begin?
Increase in permeability of the endothelium Upregulation of leukocytes and cell adhesion molecules Migration of leukocytes into arterial wall
90
What cells are recruited in the process of atherosclerosis?
Macrophages (which turn into foam cells) Fibroblasts Smooth muscle cells
91
Define atherosclerosis.
Atherosclerosis is an inflammatory fibro-proliferative disorder
92
What is the significance of chylomicron remnants with regards to atherosclerosis?
They are very good at getting into the tunica intima
93
Are most circulating lipids endogenous or exogenous?
Endogenous
94
What are chylomicrons broken down into?
Chylomicron remnants
95
Which enzyme converts phospholipids to arachidonic acid?
Phospholipase
96
What does COX convert arachidonic acid to?
Endoperoxides
97
Describe what happens to endoperoxides in platelets and in the endothelial cells.
Platelets – thromboxane synthetase converts endoperoxides to thromboxane (potent inducer of platelet aggregation) Endothelial Cells – prostacyclin synthetase converts endoperoxides to prostacyclin (important regulator of haemostasis)
98
What effect does aspirin have on this entire pathway? What effect does aspirin have on this entire pathway?
Aspirin is a COX1 inhibitor
99
State some important drug targets in platelet aggregation.
COX GlpIIb/IIIa ADP Receptor
100
State two ADP receptor antagonists.
Clopidogrel Prasugrel
101
State three GlpIIb/IIIa antagonists.
Abciximab Tirofiban Eptifibatide
102
What is the most important test for monitoring platelets and their function?
Platelet count
103
What is a common cause of spontaneous bleeding?
Autoimmune thrombocytopenia (autoimmune antibodies clear platelets from the circulation) This results in purpura, multiple bruises and ecchymoses
104
What is the normal range for platelet count?
150-400 x 109/L
105
Why do you get thrombocytopenia in leukaemia?
Leukaemic cells populate the bone marrow so it crowds out the megakaryocytes so the platelets aren’t produced in sufficient numbers
106
What is the bleeding time test used to observe?
This checks the platelet-vessel wall interaction This isn’t used any more
107
Describe the platelet aggregation test.
The platelets are stimulated with ADP/thromboxane/collagen to study their function This is used to diagnose platelet disease e.g. von Willebrand disease
108
Where is von Willebrand factor produced?
Endothelial cells and a little bit by megakaryocytes
109
What factors do megakaryocytes produce?
Factor V Von Willebrand Factor
110
Tissue factor activates the clotting cascade by converting 9 to 9a and by converting 10 to 10a. What difference does this make?
9 to 9a – slower but produces more thrombin 10 to 10a – faster
111
State two accelerating factors. What are they activated by?
Factor VIII Factor V They are activated by trace amounts of thrombin
112
Which factors are activated on the surface of the platelet? Describe how this works.
10 to 10a 2 to 2a (prothrombin to thrombin) For 9a to activate 10 it needs to come in close proximity with 10. They both bind to the surface of the platelet mediated by calcium ions, andfactor VIIIa bring the two close together so that 9a can proteolytically cleave 10 to 10a Factor Va does the same with 10a and 2 (prothrombin)
113
Which factors are affected by warfarin?
2, 7, 9, 10
114
What is common to all of these factors and what is the significance of this common feature?
They have a cluster of glutamic acid The glutamic acid is recognised by an enzyme in the liver and undergoes post-translational modification in the presence of vitamin K to Gamma-carboxyglutamic acid Once this extra carboxyl group is added, calcium can facilitate the binding of gamma carboxyglutamic acid to the activated platelet membrane phospholipid
115
How does warfarin actually inhibit the post-translational modification of these factors?
Warfarin inhibits vitamin K epoxide reductase thus inhibiting the gamma carboxylation of factors 2, 7, 9 and 10
116
Which factors are inhibited by anti-thrombin?
2, 9, 10, 11
117
What effect does heparin have on anti-thrombin?
Heparin potentiates the action of anti-thrombin
118
In what situation is heparin used?
Heparin is used for immediate anticoagulation in venous thrombosis and pulmonary embolism
119
Describe how anti-thrombin inhibits the clotting factors.
Anti-thrombin has a reactive loop that irreversibly inhibits the active site on the clotting factors So anti-thrombin acts as a scavenger in stopping inappropriate action of clotting factors
120
How does heparin potentiate the action of anti-thrombin and why is the chain length important?
Heparin is a linear negatively charged polysaccharide Once bound to anti-thrombin it changes the position of the reactive loop and makes the inhibition occur faster When inhibiting factor 10a, a relatively SHORT chain of heparin is sufficient (low molecular weight heparin) When inhibiting thrombin, you require a LARGE chain (standard/unfractionated heparin) NOTE: standard/unfractionated heparin inhibits either Factor 10a or thrombin
121
State three laboratory tests for blood coagulation.
Activated Partial Thromboplastin Time (APTT) Prothrombin Time (PT) Thrombin Clotting Time (TCT)
122
What do each of these laboratory tests represent?
APTT – detects abnormalities in the INTRINSIC and COMMON pathways (coagulation is triggered by activation of factor 12) PT – detects abnormalities in the EXTRINSIC and COMMON pathways (tissue factor is added to trigger the extrinsic pathway) TCT – shows abnormality in the fibrinogen  fibrin conversion (not important any more)
123
What are the main uses of these laboratory tests?
APTT and PT are used together for screening causes of bleeding disorders APTT is used to monitor heparin therapy for thrombosis PT is used to monitor warfarin treatment
124
What two proteins assemble on the surface of a clot to allow fibrinolysis to take place? Where are these proteins made?
Plasminogen Tissue Plasminogen Activator (tPA) Plasminogen is a plasma protein tPA is produced by endothelial cells
125
What is produced from the break down of the fibrin clot and how does this level change in DIC?
Fibrin degradation products (FDP) This is elevated in DIC
126
What factors are used in therapeutic thrombolysis of myocardial infarction?
tPA and bacterial activator streptokinase
127
Describe the function of the Protein C anticoagulant pathway.
Thrombin also has a role in anticoagulation It binds to thrombomodulin on the surface of endothelial cells and by binding to thrombomodulin it activates protein C, which, along with co-factor protein S, INACTIVATES FACTOR Va and FACTOR VIIIa

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